Androgen deprivation is a common treatment for persons with prostate cancer. Various non-steroidal antiandrogens are known for use in the treatment of prostate cancer. For example, bicalutamide, which may be among the most commonly used non-steroidal antiandrogens in the world, is typically used in the treatment of prostate cancer. Bicalutamide is commercially available as Casodex® (bicalutamide) from Zeneca Pharmaceuticals.
The chemical name of bicalutamide is N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-propanamide,(+−). The structural formula of bicalutamide is:
The β-carbon atom in the propanamide is a chiral carbon. As a result, bicalutamide is an optically active compound.
Optically active compounds have the ability to rotate the plane of polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (−) are used to denote the optical rotation of the compound (i.e., the direction in which a plane of polarized light is rotated by the optically active compound). The l or (−) prefix indicates that the compound is levorotatory (i.e., rotates the plane of polarized light to the left or counterclockwise) while the d or (+) prefix means that the compound is dextrarotatory (i.e., rotates the plane of polarized light to the right or clockwise). The sign of optical rotation, (−) and (+), is not related to the absolute configuration of the molecule, R and S.
Optically active compounds, such as bicalutamide, exist as a pair of stereoisomers that are identical with the notable exception that they are non-superimposable mirror images of one another. A specific stereoisomer, such as the R isomer, may be referred to as an enantiomer. A mixture of R and S enantiomers may be referred to as a racemic mixture.
Bicalutamide, is presently commercially available as a racemic mixture. The racemic mixture of bicalutamide may be synthesized by various methods including, for example, the methods described in U.S. Pat. No. 4,636,505 to Tucker. Tucker further describes various derivatives and analogs of bicalutamide having antiandrogenic properties. Tucker, however, does not disclose or suggest methods for asymmetrically synthesizing enantiomers of Casodex® (bicalutamide) and/or its intermediates.
U.S. Pat. No. 5,985,868 to Gray proposes synthesizing racemic mixtures of Casodex® (bicalutamide) using methods as described in U.S. Pat. No. 4,636,505 to Tucker, and obtaining the (−) isomer of Casodex® (bicalutamide) by resolution of the enantiomers of Casodex® (bicalutamide) or of intermediates thereto using fractional crystallization or chromatography of diastereomeric esters of chiral acids. Gray notes that other standard methods of resolution such as simple crystallization and chromatographic resolution can also be used. Gray does not disclose or suggest methods of asymmetrically synthesizing enantiomers of Casodex® (bicalutamide) and/or its derivatives and/or intermediates.
In Howard Tucker et al., Resolution of the Nonsteroidal Antiandrogen 4′-Cyano-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-3′-(trifluoromethyl)- propioanilide and the Determination of the Absolute Configuration of the Active Enantiomer, 31 J. MED. CHEM. 885–887 (1988), the authors propose an asymmetric synthesis of (S)-Casodex® (bicalutamide) using the N-methacrylamide of (S)-proline as a starting material. The proposed reaction scheme is as follows:
The authors state that this approach is not suitable for the general synthesis of the active enantiomers of analogous anti-androgens, which would require the inaccessible and expensive (R)-proline as a starting material.
U.S. Pat. No. 6,019,957 to Miller et al. proposes an asymmetric synthesis of (R)-Casodex® (bicalutamide) using (R)-proline as a starting material. The proposed reaction scheme is as follows:
As noted above, (R)-proline is an inaccessible and expensive starting material. It would be desirable to provide more cost effective methods for asymmetrically synthesizing enantiomers of Casodex® (bicalutamide) and/or its derivatives and/or intermediates that do not rely on (R)-proline as a starting material.